Vagus nerve and carotid baroreceptor stimulation system

ABSTRACT

Systems and methods are provided for delivering vagus nerve stimulation and carotid baroreceptor stimulation to patients for treating chronic heart failure and hypertension. The vagus nerve stimulation and carotid baroreceptor stimulation therapies may be provided using a single implantable pulse generator, which can coordinate delivery of the therapies.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.15/680,139, filed Aug. 17, 2017, which is a Divisional of U.S. patentapplication Ser. No. 14/457,754, filed on Aug. 12, 2014, now U.S. Pat.No. 9,737,716, each of which is incorporated herein by reference in itsentirety.

FIELD

This application relates to stimulation therapies.

BACKGROUND

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF. Forinstance, VNS has been demonstrated in canine studies as efficacious insimulated treatment of AF and heart failure, such as described in Zhanget al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control andAttenuates Systemic Inflammation and Heart Failure Progression in aCanine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699(Sep. 22, 2009), the disclosure of which is incorporated by reference.The results of a multi-center open-label phase II study in which chronicVNS was utilized for CHF patients with severe systolic dysfunction isdescribed in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A Newand Promising Therapeutic Approach for Chronic Heart Failure,” EuropeanHeart Journal, 32, pp. 847-855 (Oct. 28, 2010).

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's tolerancethreshold, or tolerance zone boundary, gradually increases, allowing foran increase in intensity during subsequent titration sessions. Thetitration process can take significantly longer in practice because theincrease in intensity is generally performed by a physician or otherhealthcare provider, and thus, for every step in the titration processto take place, the patient has to visit the provider's office to havethe titration performed. Scheduling conflicts in the provider's officemay increase the time between titration sessions, thereby extending theoverall titration process, during which the patient in need of VNS doesnot receive the VNS at the full therapeutic intensity.

CHF patients frequently also suffer from hypertension. The use ofimplantable systems for electrically stimulating the carotid sinus hasbeen proposed for the treatment of hypertension. These systems utilize apulse generator implanted subcutaneously near the collarbone and carotidsinus leads placed on the carotid arteries to deliver stimulation to thecarotid baroreceptors. The use of these systems has also been proposedfor promoting the reversal of ventricular remodeling in subjects withadvanced heart failure.

Accordingly, there is a need remains for improved treatment methodsutilizing stimulation therapies for treating chronic cardiac dysfunctionand other conditions.

SUMMARY

Systems and methods are provided for delivering vagus nerve stimulationand carotid baroreceptor stimulation to patients for treating chronicheart failure and hypertension. The vagus nerve stimulation and carotidbaroreceptor stimulation therapies may be provided using a singleimplantable pulse generator, which can coordinate delivery of thetherapies to modify the stimulation parameters based on a variety offactors.

In accordance with embodiments of the present invention, an implantableneurostimulation system is provided, comprising: a pulse generationmodule comprising a control system, a vagus nerve stimulation (VNS)subsystem, and an implantable carotid baroreceptor stimulation (CBS)subsystem; a first VNS electrode assembly coupled to the pulsegeneration module, said first VNS electrode assembly configured tocouple to and deliver electrical stimulation to a vagus nerve; and afirst CBS electrode assembly coupled to the pulse generation module,said first CBS electrode assembly configured to couple to and deliverelectrical stimulation to carotid baroreceptors. In accordance with someembodiments, the control system is configured to modify a stimulationparameter of the CBS subsystem in response to detected state changes.

In accordance with embodiments of the present invention, a method ofoperating an implantable neurostimulation system is provided,comprising: delivering a vagus nerve stimulation (VNS) therapy to avagus nerve with a VNS subsystem of a pulse generation module; anddelivering a carotid baroreceptor stimulation (CBS) therapy to carotidbaroreceptors with a CBS subsystem of the pulse generation module.

In accordance with embodiments of the present invention, a method ofoperating an implantable stimulation system is provided, comprising:implanting a pulse generation module in a chest of a patient; tunnelinga lead assembly between a neck of the patient and the pulse generationmodule, said lead assembly comprising a first electrode assembly, asecond electrode assembly, and a proximal connector; through a singleincision in the neck of the patient, coupling the first electrodeassembly to a carotid artery and coupling the second electrode assemblyto a vagus nerve; and coupling the proximal connector to the pulsegeneration module.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 3.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIGS. 8A-8C are illustrative charts reflecting a heart rate response togradually increased stimulation intensity at different frequencies.

FIGS. 9A-9G illustrate front anatomical diagrams showing variousconfigurations of CB S/VNS systems, in accordance with embodiments ofthe present invention.

FIG. 10 illustrates a block diagram of an implantable pulse generationmodule, in accordance with embodiments of the present invention.

DETAILED DESCRIPTION

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, in accordance with embodiments of thepresent invention. The VNS provided through the stimulation system 11operates under several mechanisms of action. These mechanisms includeincreasing parasympathetic outflow and inhibiting sympathetic effects byinhibiting norepinephrine release and adrenergic receptor activation.More importantly, VNS triggers the release of the endogenousneurotransmitter acetylcholine and other peptidergic substances into thesynaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and anti-inflammatory effects as well as beneficialeffects at the level of the central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The stimulating nerve electrode assembly 125, preferablycomprising at least an electrode pair, is conductively connected to thedistal end of an insulated, electrically conductive lead assembly 13 andelectrodes 14. The electrodes 14 may be provided in a variety of forms,such as, e.g., helical electrodes, probe electrodes, cuff electrodes, aswell as other types of electrodes.

The implantable vagus stimulation system 11 can be remotely accessedfollowing implant through an external programmer, such as the programmer40 shown in FIG. 3 and described in further detail below. The programmer40 can be used by healthcare professionals to check and program theneurostimulator 12 after implantation in the patient 10 and to adjuststimulation parameters during the initial stimulation titration process.In some embodiments, an external magnet may provide basic controls, suchas described in commonly assigned U.S. Pat. No. 8,600,505, entitled“Implantable Device For Facilitating Control Of Electrical StimulationOf Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,”the disclosure of which is incorporated by reference. For furtherexample, an electromagnetic controller may enable the patient 10 orhealthcare professional to interact with the implanted neurostimulator12 to exercise increased control over therapy delivery and suspension,such as described in commonly-assigned U.S. Pat. No. 8,571,654, entitled“Vagus Nerve Neurostimulator With Multiple Patient-Selectable Modes ForTreating Chronic Cardiac Dysfunction,” the disclosure of which isincorporated by reference. For further example, an external programmermay communicate with the neurostimulation system 11 via other wired orwireless communication methods, such as, e.g., wireless RF transmission.Together, the implantable vagus stimulation system 11 and one or more ofthe external components form a VNS therapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. A study of the relationship between cardiac autonomic nerveactivity and blood pressure changes in ambulatory dogs is described inJ. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure inAmbulatory Dogs,” Heart Rhythm, Vol. 11(2), pp. 307-313 (February 2014).Generally, cervical vagus nerve stimulation results in propagation ofaction potentials from the site of stimulation in a bi-directionalmanner. The application of bi-directional propagation in both afferentand efferent directions of action potentials within neuronal fiberscomprising the cervical vagus nerve improves cardiac autonomic balance.Afferent action potentials propagate toward the parasympathetic nervoussystem's origin in the medulla in the nucleus ambiguus, nucleus tractussolitarius, and the dorsal motor nucleus, as well as towards thesympathetic nervous system's origin in the intermediolateral cell columnof the spinal cord. Efferent action potentials propagate toward theheart 17 to activate the components of the heart's intrinsic nervoussystem. Either the left or right vagus nerve 15, 16 can be stimulated bythe stimulation system 11. The right vagus nerve 16 has a moderatelylower (approximately 30%) stimulation threshold than the left vagusnerve 15 for heart rate effects at the same stimulation frequency andpulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy Demipulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, Tex., although other manufactures and typesof implantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in two sizes based, for example, on a helicalelectrode inner diameter, although other manufactures and types ofsingle-pin receptacle-compatible therapy leads and electrodes could alsobe used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, such as firmwarewithin which the stimulation parameters and timing cycles can be stored.Other electronic circuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown) and aset of screws 26.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heart beat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28. During implantation, the connector pin 28 isguided through the receptacle 25 into the header 24 and securelyfastened in place using the set screws 26 to electrically couple thelead assembly 13 to the neurostimulator 12. On a distal end, the leadassembly 13 terminates with the electrode 14, which bifurcates into apair of anodic and cathodic electrodes 62 (as further described infrawith reference to FIG. 4). In one embodiment, the lead connector 27 ismanufactured using silicone and the connector pin 28 is made ofstainless steel, although other suitable materials could be used, aswell. The insulated lead body 13 utilizes a silicone-insulated alloyconductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a monopolar cathode,a proximal anode and a distal cathode, or a proximal cathode and adistal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters, suchas described in commonly-assigned U.S. Pat. Nos. 8,600,505 and8,571,654, cited supra. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. The programming computer 41 may further beconfigured to receive inputs, such as physiological signals receivedfrom patient sensors (e.g., implanted or external). These sensors may beconfigured to monitor one or more physiological signals, e.g., vitalsigns, such as body temperature, pulse rate, respiration rate, bloodpressure, etc. These sensors may be coupled directly to the programmingcomputer 41 or may be coupled to another instrument or computing devicewhich receives the sensor input and transmits the input to theprogramming computer 41. The programming computer 41 may monitor,record, and/or respond to the physiological signals in order toeffectuate stimulation delivery in accordance with embodiments of thepresent invention.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

FIG. 4 is a diagram showing the helical electrodes 14 provided as on thestimulation lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16in situ 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode. In addition, an anchor tether 53 is fastened over the lead bodies57, 58 that maintains the helical electrodes' position on the vagusnerve 61 following implant. In one embodiment, the conductors of theelectrodes 51, 52 are manufactured using a platinum and iridium alloy,while the helical materials of the electrodes 51, 52 and the anchortether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Patent application entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7,2011, published as U.S. Patent Publication no. 2013-0158618 A1, pending,the disclosure of which is incorporated by reference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.Patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. Patentapplication entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, U.S. PatentPublication No. 2013-0158616 A1, pending, and U.S. Patent applicationentitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction withBounded Titration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, U.S.Patent Publication No. 2013-0158617 A1, pending, the disclosures ofwhich are incorporated by reference. Finally, the neurostimulator 12 canbe used to counter natural circadian sympathetic surge upon awakeningand manage the risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, such as respectively described incommonly-assigned U.S. Patent application entitled “ImplantableNeurostimulator-Implemented Method For Enhancing Heart Failure PatientAwakening Through Vagus Nerve Stimulation,” Ser. No. 13/673,811, filedon Nov. 9, 2012, pending, the disclosure of which is incorporated byreference.

The VNS stimulation signal may be delivered as a therapy in amaintenance dose having an intensity that is insufficient to elicitundesirable side effects, such as cardiac arrhythmias. The VNS can bedelivered with a periodic duty cycle in the range of 2% to 89% with apreferred range of around 4% to 36% that is delivered as a low intensitymaintenance dose. Alternatively, the low intensity maintenance dose maycomprise a narrow range approximately at 17.5%, such as around 15% to25%. The selection of duty cycle is a tradeoff among competing medicalconsiderations. The duty cycle is determined by dividing the stimulationON time by the sum of the ON and OFF times of the neurostimulator 12during a single ON-OFF cycle. However, the stimulation time may alsoneed to include ramp-up time and ramp-down time, where the stimulationfrequency exceeds a minimum threshold (as further described infra withreference to FIG. 7).

FIG. 5 is a graph 70 showing, by way of example, the relationshipbetween the targeted therapeutic efficacy 73 and the extent of potentialside effects 74 resulting from use of the implantable neurostimulator 12of FIG. 1, after the patient has completed the titration process. Thegraph in FIG. 5 provides an illustration of the failure of increasedstimulation intensity to provide additional therapeutic benefit, oncethe stimulation parameters have reached the neural fulcrum zone, as willbe described in greater detail below with respect to FIG. 8. As shown inFIG. 5, the x-axis represents the duty cycle 71. The duty cycle isdetermined by dividing the stimulation ON time by the sum of the ON andOFF times of the neurostimulator 12 during a single ON-OFF cycle.However, the stimulation time may also include ramp-up time andramp-down time, where the stimulation frequency exceeds a minimumthreshold (as further described infra with reference to FIG. 7). Whenincluding the ramp-up and ramp-down times, the total duty cycle may becalculated as the ON time plus the ramp-up and ramp-down times dividedby the OFF time, ON time, and ramp-up and ramp-down times, and may be,e.g., between 15% and 30%, and more specifically approximately 23%. They-axis represents physiological response 72 to VNS therapy. Thephysiological response 72 can be expressed quantitatively for a givenduty cycle 71 as a function of the targeted therapeutic efficacy 73 andthe extent of potential side effects 74, as described infra. The maximumlevel of physiological response 72 (“max”) signifies the highest pointof targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty range 83is a function 84 of the intersection 75 of the targeted therapeuticefficacy 73 and the extent of potential side effects 74. The therapeuticoperating points 82 can be expressed quantitatively for a given dutycycle 81 as a function of the values of the targeted therapeuticefficacy 73 and the extent of potential side effects 74 at their pointof intersection in the graph 70 of FIG. 5. The optimal therapeuticoperating point 85 (“max”) signifies a tradeoff that occurs at the pointof highest targeted therapeutic efficacy 73 in light of lowest potentialside effects 74 and that point will typically be found within the rangeof a 5% to 30% duty cycle 81. Other expressions of duty cycles andrelated factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in a lowlevel maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally-mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μSecdelivers between 0.02 mA and 50 mA of output current at a signalfrequency of about 10 Hz, although other therapeutic values could beused as appropriate. In general, the stimulation signal delivered to thepatient may be defined by a stimulation parameter set comprising atleast an amplitude, a frequency, a pulse width, and a duty cycle.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation.

In another embodiment, as shown in FIG. 7, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97 and a ramp-down time 98 that respectively precede and follow theON time 92. Under this embodiment, the ON time 92 is considered to be atime during which the neurostimulator 12 is ON and delivering pulses ofstimulation at the full output current 96. Under this embodiment, theOFF time 95 is considered to comprise the ramp-up time 97 and ramp-downtime 98, which are used when the stimulation frequency is at least 10Hz, although other minimum thresholds could be used, and both ramp-upand ramp-down times 97, 98 last two seconds, although other time periodscould also be used. The ramp-up time 97 and ramp-down time 98 allow thestrength of the output current 96 of each output pulse to be graduallyincreased and decreased, thereby avoiding deleterious reflex behaviordue to sudden delivery or inhibition of stimulation at a programmedintensity.

Therapeutic vagus neural stimulation has been shown to providecardioprotective effects. Although delivered in a maintenance dosehaving an intensity that is insufficient to elicit undesirable sideeffects, such as cardiac arrhythmias, ataxia, coughing, hoarseness,throat irritation, voice alteration, or dyspnea, therapeutic VNS cannevertheless potentially ameliorate pathological tachyarrhythmias insome patients. Although VNS has been shown to decrease defibrillationthreshold, VNS has not been shown to terminate VF in the absence ofdefibrillation. VNS prolongs ventricular action potential duration, somay be effective in terminating VT. In addition, the effect of VNS onthe AV node may be beneficial in patients with AF by slowing conductionto the ventricles and controlling ventricular rate.

Neural Fulcrum Zone

As described above, autonomic regulation therapy results in simultaneouscreation of action potentials that simultaneously propagate away fromthe stimulation site in afferent and efferent directions within axonscomprising the cervical vagus nerve complex. Upon stimulation of thecervical vagus nerve, action potentials propagate away from thestimulation site in two directions, efferently toward the heart andafferently toward the brain. Different parameter settings for theneurostimulator 12 may be adjusted to deliver varying stimulationintensities to the patient. The various stimulation parameter settingsfor current VNS devices include output current amplitude, signalfrequency, pulse width, signal ON time, and signal OFF time.

When delivering neurostimulation therapies to patients, it is generallydesirable to avoid stimulation intensities that result in eitherexcessive tachycardia or excessive bradycardia. However, researchershave typically utilized the patient's heart rate changes as a functionalresponse indicator or surrogate for effective recruitment of nervefibers and engagement of the autonomic nervous system elementsresponsible for regulation of heart rate, which may be indicative oftherapeutic levels of VNS. Some researchers have proposed that heartrate reduction caused by VNS stimulation is itself beneficial to thepatient.

In accordance with some embodiments, a neural fulcrum zone isidentified, and neurostimulation therapy is delivered within the neuralfulcrum zone. This neural fulcrum zone corresponds to a combination ofstimulation parameters at which autonomic engagement is achieved but forwhich a functional response determined by heart rate change is nullifieddue to the competing effects of afferently and efferently-transmittedaction potentials. In this way, the tachycardia-inducing stimulationeffects are offset by the bradycardia-inducing effects, therebyminimizing side effects such as significant heart rate changes whileproviding a therapeutic level of stimulation. One method of identifyingthe neural fulcrum zone is by delivering a plurality of stimulationsignals at a fixed frequency but with one or more other parametersettings changed so as to gradually increase the intensity of thestimulation.

FIGS. 8A-8C provide illustrative charts reflecting the location of theneural fulcrum zone. FIG. 8A is a chart 800 illustrating a heart rateresponse in response to such a gradually increased intensity at a firstfrequency, in accordance with embodiments of the present invention. Inthis chart 800, the x-axis represents the intensity level of thestimulation signal, and the y-axis represents the observed heart ratechange from the patient's baseline basal heart rate observed when nostimulation is delivered. In this example, the stimulation intensity isincreased by increasing the output current amplitude.

A first set 810 of stimulation signals is delivered at a first frequency(e.g., 10 Hz). Initially, as the intensity (e.g., output currentamplitude) is increased, a tachycardia zone 851-1 is observed, duringwhich period, the patient experiences a mild tachycardia. As theintensity continues to be increased for subsequent stimulation signals,the patient's heart rate response begins to decrease and eventuallyenters a bradycardia zone 853-1, in which a bradycardia response isobserved in response to the stimulation signals. As described above, theneural fulcrum zone is a range of stimulation parameters at which thefunctional effects from afferent activation are balanced with ornullified by the functional effects from efferent activation to avoidextreme heart rate changes while providing therapeutic levels ofstimulation. In accordance with some embodiments, the neural fulcrumzone 852-1 can be located by identifying the zone in which the patient'sresponse to stimulation produces either no heart rate change or a mildlydecreased heart rate change (e.g., <5% decrease, or a target number ofbeats per minute). As the intensity of stimulation is further increasedat the fixed first frequency, the patient enters an undesirablebradycardia zone 853-1. In these embodiments, the patient's heart rateresponse is used as an indicator of autonomic engagement. In otherembodiments, other physiological responses may be used to indicate thezone of autonomic engagement at which the propagation of efferent andafferent action potentials are balanced, the neural fulcrum zone.

FIG. 8B is a chart 860 illustrating a heart rate response in response tosuch a gradually increased intensity at two additional frequencies, inaccordance with embodiments of the present invention. In this chart 860,the x-axis and y-axis represent the intensity level of the stimulationsignal and the observed heart rate change, respectively, as in FIG. 8A,and the first set 810 of stimulation signals from FIG. 8A is also shown.

A second set 810 of stimulation signals is delivered at a secondfrequency lower than the first frequency (e.g., 5 Hz). Initially, as theintensity (e.g., output current amplitude) is increased, a tachycardiazone 851-2 is observed, during which period, the patient experiences amild tachycardia. As the intensity continues to be increased forsubsequent stimulation signals, the patient's heart rate response beginsto decrease and eventually enters a bradycardia zone 853-2, in which abradycardia response is observed in response to the stimulation signals.The low frequency of the stimulation signal in the second set 820 ofstimulation signals limits the functional effects of nerve fiberrecruitment and, as a result, the heart response remains relativelylimited. Although this low frequency stimulation results in minimal sideeffects, the stimulation intensity is too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered.

A third set of 830 of stimulation signals is delivered at a thirdfrequency higher than the first and second frequencies (e.g., 20 Hz). Aswith the first set 810 and second set 820, at lower intensities, thepatient first experiences a tachycardia zone 851-3. At this higherfrequency, the level of increased heart rate is undesirable. As theintensity is further increased, the heart rate decreases, similar to thedecrease at the first and second frequencies but at a much higher rate.The patient first enters the neural fulcrum zone 852-3 and then theundesirable bradycardia zone 853-3. Because the slope of the curve forthe third set 830 is much steeper than the second set 820, the region inwhich the patient's heart rate response is between 0% and −5% (e.g., theneural fulcrum zone 852-3) is much narrower than the neural fulcrum zone852-2 for the second set 820. Accordingly, when testing differentoperational parameter settings for a patient by increasing the outputcurrent amplitude by incremental steps, it can be more difficult tolocate a programmable output current amplitude that falls within theneural fulcrum zone 852-3. When the slope of the heart rate responsecurve is high, the resulting heart rate may overshoot the neural fulcrumzone and create a situation in which the functional response transitionsfrom the tachycardia zone 851-3 to the undesirable bradycardia zone853-3 in a single step. At that point, the clinician would need toreduce the amplitude by a smaller increment or reduce the stimulationfrequency in order to produce the desired heart rate response for theneural fulcrum zone 852-3.

FIG. 8C is a chart 880 illustrating mean heart rate response surfaces inconscious, normal dogs during 14 second periods of right cervical vagusVNS stimulation ON-time. The heart rate responses shown in z-axisrepresent the percentage heart rate change from the baseline heart rateat various sets of VNS parameters, with the pulse width the pulse widthset at 250 μsec, the pulse amplitude ranging from 0 mA to 3.5 mA(provided by the x-axis) and the pulse frequency ranging from 2 Hz to 20Hz (provided by the y-axis). Curve 890 roughly represents the range ofstimulation amplitude and frequency parameters at which a null response(i.e., 0% heart rate change from baseline) is produced. This nullresponse curve 890 is characterized by the opposition of functionalresponses (e.g., tachycardia and bradycardia) arising from afferent andefferent activation.

Closed-Loop Neurostimulation

As described above, embodiments of the implanted device may include aphysiological sensor, such as a heart rate sensor or a blood pressuresensor, configured to monitor a physiological signal from the patientover extended periods of time on an ambulatory basis. In accordance withembodiments of the present invention, the implanted device may beconfigured to adjust stimulation parameters to maintain stimulation inthe neural fulcrum zone based on detected changes in the physiologicalresponse to stimulation.

In some embodiments described above, the identification of the neuralfulcrum zone and the programming of the stimulation parameters todeliver stimulation signals in the neural fulcrum zone may be performedin a clinic by a health care provider. In some embodiments, theimplanted medical device may be configured to automatically monitor thepatient's physiological response using an implanted physiological sensorto initially identify the neural fulcrum zone and set the stimulationparameters to deliver signals in the neural fulcrum zone. In addition,under certain circumstances, the patient's physiological response tothose initial stimulation parameters may change. This change could occuras the stimulation is chronically delivered over an extended period oftime as the patient's body adjusts to the stimulation. Alternatively,this change could occur as a result of other changes in the patient'scondition, such as changes in the patient's medication, disease state,circadian rhythms, or other physiological change.

If the changes in the patient's response to stimulation results in achange in the patient's response curve, the initially identifiedstimulation parameters may no longer deliver stimulation in the neuralfulcrum zone. Therefore, it may be desirable for the implanted medicaldevice to automatically adjust one or more stimulation parameters (e.g.,pulse amplitude) so that subsequent stimulation signals may be deliveredin the neural fulcrum zone. For example, in embodiments described above,where the monitored physiological response is the patient's heart rate,then if tachycardia is later detected in response to stimulation signalsthat had previously resulted in a transition heart rate response, theIMD may be configured to automatically increase the pulse amplitude (orother stimulation parameters) until a transition heart rate response isagain detected. Subsequent stimulation may continue to be deliveredusing the new stimulation parameters until another change in thepatient's physiological response is detected.

In some embodiments, the patient's physiological response may besubstantially continuously monitored. In other embodiments, thepatient's physiological response may be monitored on a periodic basis,such as, for example, every minute, hour, day, or other periodic oraperiodic schedule that may be desired in order to provide the desiredmonitoring schedule. In other embodiments, the patient's physiologicalresponse may be monitored in response to a control signal delivered byan external device, such as a control magnet or wireless data signalfrom a programming wand. The external control signal to initiatemonitoring may be delivered when it is desired to monitor thephysiological response when a patient condition is changing, such aswhen the patient is about to take a medication, is about to go to sleep,or has just awoken from sleep. In some embodiments, the external controlsignal may be used by the patient when an automatically increasingstimulation intensity in response to monitoring physiological signals iscausing undesirable side effects. When the IMD receives such a controlsignal, the IMD may be programmed to automatically reduce thestimulation intensity until the side effects are alleviated (asindicated, for example, by a subsequent control input).

Implantable VNS and Carotid Baroreceptor Stimulation System

Patients suffering from chronic heart failure frequently also sufferfrom hypertension. Hypertension causes a distortion of the arterialwall, which stimulates stretch-sensitive baroreceptors contained in thecarotid artery. The application of an electrical field to the carotidsinus wall to electrically stimulate the carotid baroreceptor has beenproposed as a therapy for blood pressure reduction. In accordance withembodiments of the present invention, combination stimulation systemsare provided which deliver VNS stimulation for treating CHF, asdescribed in greater detail above, along with carotid baroreceptorstimulation (CBS) for treating hypertension, as will be described ingreater detail below. Combining the VNS functionality with the CBSfunctionality into a single implantable device provides an integratedtherapy system for two common comorbidities, and can minimize implantsize, invasiveness, and complexity of implantation surgery, as well asprovide other therapeutic advantages described below.

FIGS. 9A-9G are front anatomical diagrams showing, by way of example,various implantable VNS/CBS systems in accordance with embodiments ofthe present invention. FIG. 9A provides a simplified illustration ofcertain anatomic features of a human subject 10 pertinent to the VNS/CBSstimulation systems. The left ventricle of the subject's heart pumpsoxygenated blood into the aortic arch 901. The left common carotidartery 902L and the right common carotid artery 902R extend from theaortic arch 901 towards the brain. The left common carotid artery 902Lbifurcates into the left internal carotid artery 906L and the leftexternal carotid artery 907L at the left carotid sinus 908L, and theright common carotid artery 902R bifurcates into the right internalcarotid artery 906R and the right external carotid artery 907R at theright carotid sinus 908R. The left carotid sinus nerve 905L terminatesat the left carotid baroreceptors and the right carotid sinus nerve 905Rterminates at the right carotid baroreceptors 909R. The carotidbaroreceptors are sensory nerve endings in the wall of the carotidsinus, which are sensitive to stretching of the wall resulting fromincreased pressure from within. The carotid baroreceptors are connectedto the brain via the nervous system and function as the receptor ofcentral reflex mechanisms that tend to reduce that pressure. The leftvagus nerve 910L runs through the patient's neck roughly parallel to thecommon carotid artery 902L and in close proximity to the left carotidbaroreceptor, and the right vagus nerve 910R runs roughly parallel tothe common carotid artery 902R and in close proximity to the rightcarotid baroreceptor 909R.

FIG. 9A shows a single-lead VNS/CBS system 900 a, in accordance withembodiments of the present invention. The system 900 a comprises a pulsegeneration module 920 a having a CBS electrode assembly 940 a forproviding CBS stimulation, and a VNS electrode assembly 950 a forproviding VNS stimulation, as described above with respect to FIG. 1. Inthe embodiment illustrated in FIG. 9A, the CBS electrode assembly 940 aand VNS electrode assembly 950 a are provided as part of a single leadassembly 930 a, which has single connector coupled to a header on thepulse generation module 920 a. In other embodiments, such as thosedescribed below, other configurations may be used.

The CBS electrode assembly 940 a may comprise any type of electrodesuitable for delivering electrical stimulation to activate the carotidbaroreceptors to induce the baroreflex system. A variety of electrodeconfigurations have been used by others to stimulate the baroreceptorsand may be suitable for use various embodiments. For example, the CBSelectrode assembly 940 a may comprise a coil or patch electrodepositioned over the exterior of the carotid sinus 908L near the carotidbifurcation. The VNS electrode assembly 950 a may comprise any type ofelectrode suitable for delivering electrical stimulation to the vagusnerve 910L, such as, e.g., a bipolar electrode described above withrespect to FIG. 1A. The first lead assembly 930 a may comprise asilicone or polyurethane insulation surrounding conductive leads whichconduct electrical current between the pulse generation module 920 a andthe electrode assemblies. Any of a variety of electrode assemblies maybe used in accordance with embodiments of the present invention.

Sensing electrodes (not shown) may also be provided at an intermediateposition along the lead assembly 930 a or as part of a separate leadassembly for detecting subcutaneous electrocardiographic (ECG) signals.This detected ECG can be used to determine the patient's heart rate,including changes to the heart rate in response to either VNS or CBSstimulation or to other changes in the patient's physical state. Inother embodiments, one or more of the stimulation electrode assemblies(e.g., the CBS electrode assembly 940 a or the VNS electrode assembly950 a) and/or the housing of the pulse generation module 920 a may beused for sensing ECG in addition to the sensing electrodes to provideadditional ECG sensing vectors, or in place of the dedicated sensingelectrodes to reduce the total number of electrodes in the system 900 a.In some embodiments, a transvascular pressure sensor may be used measuredeflections in a vascular wall in order to determine arterial bloodpressure. In some embodiments, this transvascular pressure sensor may beintegrated into the CBS electrode assembly, such that both the pressuresensing components and the CBS electrode contacts may be integrated intoa single cuff structure that is positioned around the carotid sinus.

FIG. 10 is a simplified block diagram of the implantable pulsegeneration module 920 a. The pulse generation module 920 a comprises aCBS subsystem 1010, a VNS subsystem 1020, a header assembly 1040, acontrol system 1030, a memory 1032, a communications interface 1034, abattery 1036, and an ECG sensing module 1016. The control system 1102comprises a processor and other logic programmed to control theoperation of the pulse generation module 920 a. The memory 1032 may beused to store operational parameters for the pulse generation module 920a and data regarding sensed physiological signals and stimulationdelivery. The communications interface 1034 may be used to communicatewith other devices, such as an external programmer for programming andretrieving data from the module 920 a, or one or more implanted orexternal sensors for detecting ECG or other patient physiologicalsignals. The communications interface 1034 may comprise any of a varietyof wireless communication systems suitable for use with an implanteddevice. The battery 1036 may comprise any type of battery suitable forpowering the module 920 a, such as a lithium carbon monofluoride primarybattery or a rechargeable secondary cell battery. Because the powerdemands of CBS and VNS differ, in some embodiments, separate batteriesmay be used for powering the CBS subsystem 1010 and the VNS subsystem1020.

The CBS subsystem 1010 comprises a CBS pulse generator 1012 and the VNSsubsystem 1020 comprises a VNS pulse generator 1022. The CBS pulsegenerator 1012 and the VNS pulse generator 1022 are conceptuallyillustrated in FIG. 10 as separate blocks, but may be implemented asseparate hardware components (e.g., separate logic and electroniccomponents), or may be implemented using common hardware components.

In various embodiments, the pulse generation module 920 a may beimplanted in a variety of locations within the patient's body. Forexample, the module 920 a may be positioned subcutaneously on either theleft side, right side, or medial position in the patient's chest betweenthe skin and the rib cage, proximal to, distal from, or overlapping thesternum, in an axillary location, or in a posterior location. Theembodiment illustrated in FIG. 9A utilizes a single lead assembly 930 aso that only a single lead is tunneled through the patient's neck to thepulse generation module 920 a. This can reduce the challenges associatedwith tunneling multiple leads through the patient's neck. Because of theclose proximity of the vagus nerve 910L to the left carotidbaroreceptors, the two neural targets for stimulation are located in thesame general region in the patient's neck. Accordingly, the implantationof the CBS electrode assembly 940 a for providing CBS stimulation andthe VNS electrode assembly 950 a for providing VNS stimulation may beperformed via a single incision in the patient's neck, therebyminimizing the invasiveness of the implantation surgery. In someembodiments, the surgical techniques used for coupling the CBS electrodeassembly 940 a for providing CBS stimulation and the VNS electrodeassembly 950 a for providing VNS stimulation may be very similar,thereby minimizing the amount of additional surgical training requiredfor the implanting physician.

Any techniques for carotid baroreceptor stimulation may be utilized inthe operation of the CBS function of VNS/CBS system, in accordance withembodiments of the present invention. The CBS stimulation intensity maybe configured to deliver stimulation at any desired therapeutic level.The output signal may be, for example, constant current or constantvoltage. In embodiments using a modulated signal, wherein the outputsignal comprises, for example, a series of pulses, any of thestimulation pulse parameters may be adjusted, including, for example,amplitude, frequency, pulse width, pulse waveform, pulse polarity, andpulse phase (e.g., monophasic or biphasic). For example, the CBSsubsystem 1010 may deliver a rectangular pulse stimulation signal at afixed intensity, e.g., with a stimulation amplitude ranging fromapproximately 0.5 mA to approximately 7.0 mA, a stimulation frequencybetween approximately 20 Hz and approximately 100 Hz, and a pulse widthof approximately 500 μsec.

In some embodiments, the output signal for CBS stimulation may have afixed waveform and intensity delivered intermittently at a high dutycycle 24 hours a day. In accordance with other embodiments of thepresent invention, the VNS and CBS stimulation therapies may be adjustedbased on time of day, patient status, or other variable, and the VNS andCBS stimulation may be delivered in a coordinated fashion.

Humans typically have a greater metabolic demand during waking hoursthan during periods of sleep. Due to variation in a subject's activitylevels over the course of the day, heart rate regulation is morecomplicated than during periods of sleep, when the subject's metabolicfluctuations decrease. In addition, during periods of sleep, thesubject's average heart rate and blood pressure are generally lower thanduring waking hours. Accordingly, in some embodiments, it may bedesirable to modify either or both the CBS and VNS stimulationparameters to optimize for the variable demands of sleep and wake time.In some embodiments, the pulse generation module 920 a may include aninternal clock, so the periods of sleep and wake may be estimated basedon the time of day, such that a certain window of time during the night(e.g., between 1 am-6 am or other time period during which the subject10 typically sleeps) are assumed to be periods of sleep and theremaining times are assumed to be periods of awake time. In otherembodiments, sensors may be used in place of or in addition to theinternal clock to estimate sleep/wake times. For example, the controlsystem 1030 may assume the subject is sleeping based on the heart ratechanges detected by the ECG sensing module 1016. A reduced heart rateover an extended period of time or during evening hours may indicatethat the subject is asleep. The pulse generation module 920 a may alsoutilize movement sensors, such as accelerometers and inclinometers, toestimate the subject's sleep/wake state. For example, an absence ofmovement in the subject or a prolonged period of a reclined position maybe indicative of sleep, particularly when observed during periods ofreduced heart rate.

In accordance with embodiments of the present invention, differentstimulation parameters may be used depending on the subject's estimatedsleep/wake state. In some embodiments, the intensity of the CBS and/orVNS stimulation may be reduced at night due to the decreased metabolicdemands. In other embodiments, the intensity of the CBS and/or VNSstimulation may be increased at night due to a potential increase in thesubject's tolerance for side effects resulting from the increasedstimulation intensity during sleep.

In other embodiments, different stimulation parameters may be useddepending on changes in the patient's physiological state. It may bedesirable to increase or decrease one or both of the CBS and VNSstimulation parameters in response to detected state changes. If boththe CBS and VNS therapies are being modified, the increases or decreasesin the stimulation parameters may occur simultaneously or alternately.In some embodiments, different stimulation parameters may be useddepending on the patient's activity level, which may be estimated basedon the patient's heart rate and/or movement. In this case, the CBStherapy may be temporarily suspended during periods of increasedactivity levels, which would be indicative of exercise or other vigorousactivity.

The control system may be configured to coordinate the delivery of theCBS and VNS therapies. In some embodiments, it may be desirable for theCBS and VNS therapies to be delivered with the same stimulationparameter settings. In other embodiments, it may be desirable for thetherapies to be delivered with different parameter settings. Forexample, the control system may configured to activate the VNS subsystemto deliver electrical stimulation with a first stimulation parameter andto activate the CBS subsystem to deliver electrical stimulation with asecond stimulation parameter different than the first stimulationparameter. The first and second stimulation parameters may correspond toone or more of the following parameters: stimulation amplitude,stimulation frequency, stimulation pulse width, or stimulation dutycycle.

As described above, any variety of system configurations may be used invarious embodiments. FIG. 9B is front anatomical diagram showing asingle-lead VNS/CBS system 900 b, in accordance with other embodimentsof the present invention. The system 900 b comprises a pulse generationmodule 910 b having a single lead assembly 920 b, similar to leadassembly 920 a in FIG. 9A, except that the CBS electrode assembly 940 bis provided at a distal end of the lead assembly 920 b, and the VNSelectrode assembly 950 b is provided at an intermediate point betweenthe CBS electrode assembly 940 b and the pulse generation module 920 b.This arrangement may be preferable over the arrangement illustrated inFIG. 9A, depending on the desired routing of the lead assembly 920 a toreach the two neural stimulation targets.

FIG. 9C is front anatomical diagram showing a single bifurcated leadVNS/CBS system 900 c, in accordance with other embodiments of thepresent invention. The system 900 c comprises a bifurcated lead assembly930 c, which comprises a bifurcated portion 932 c leading to a CBS leadportion 934 c and a VNS lead portion 935 c. The CBS electrode assembly940 c is provided at a distal end of the CBS lead portion 934 c and VNSelectrode assembly 950 c is provided at a distal end of the VNS leadportion 935 c. This configuration may advantageously provide a singlelead body to tunnel between the pulse generation module 920 c and thesubject's neck, while also providing increased flexibility inpositioning the CBS electrode assembly 940 c and VNS electrode assembly950 c at the desired location in the subject.

FIG. 9D is front anatomical diagram showing a two lead VNS/CBS system920 d, in accordance with other embodiments of the present invention.The system 920 d comprises a pulse generation module 910 d coupled tothe proximal connector of a CBS lead assembly 936 d and the proximalconnector of a separate VNS lead assembly 937 d. The CBS electrodeassembly 940 d is provided at a distal end of the CBS lead assembly 936d and VNS electrode assembly 950 d is provided at a distal end of theVNS lead assembly 937 d. This configuration may advantageously provideincreased flexibility in positioning the CBS electrode assembly 940 dand VNS electrode assembly 950 d at the desired location in the subject.Although FIG. 9D shows both the CBS electrode assembly 940 d and VNSelectrode assembly 950 d positioned on the left side of the subject'sneck, in other embodiments, a first one of the electrode assemblies maybe positioned on an opposite side of the subject's neck from a secondone of the electrode assemblies.

FIG. 9E is front anatomical diagram showing a two lead, bilateralVNS/CBS system 900 e, in accordance with other embodiments of thepresent invention. The system 900 e comprises a pulse generation module920 e coupled to a proximal connector of a CBS lead assembly 936 e and aproximal connector of a VNS lead assembly 937 e. In the illustratedembodiment, the CBS lead assembly 936 e comprises a bifurcated portion932 e leading to a first CBS lead portion 934 e-1 and a second CBS leadportion 934 e-2. A first CBS electrode assembly 940 e-1 at the distalend of the first CBS lead portion 934 e-1 is positioned to stimulate thesubject's left baroreceptors, and a second CBS electrode assembly 940e-2 at the distal end of the second CBS lead portion 934 e-2 ispositioned to stimulate the subject's right baroreceptors. Thisembodiment enables the bilateral stimulation of the carotidbaroreceptors, along with the stimulation of the left vagus nerve.

FIG. 9F is front anatomical diagram showing a two lead, bilateralVNS/CBS system 900 f, in accordance with other embodiments of thepresent invention. The system 900 f comprises a pulse generation module920 f coupled to a proximal connector of a first bifurcated leadassembly 936 f-1 and a proximal connector of a second bifurcated leadassembly 936 f-2. In the illustrated embodiment, the first lead assembly936 f-1 comprises a bifurcated portion 932 f-1 leading to a first VNSlead portion 935 f-1 and a first CBS lead portion 935 f-2, which have afirst VNS electrode assembly 950 f-1 and a first CBS electrode assembly940 f-1 provided at distal ends thereof, respectively. A second leadassembly 936 f-2 similar to the first lead assembly 936 f-1, andcomprises a bifurcated portion 932 f-2 leading to a second VNS leadportion 934 f-2 and a second CBS lead portion 934 f-2, which have asecond VNS electrode assembly 950 f-2 and a second CBS electrodeassembly 940 f-2 provided at distal ends thereof, respectively. Thisconfiguration enables bilateral CBS stimulation and bilateral VNSstimulation.

FIG. 9G is front anatomical diagram showing a single lead, single cuffVNS/CBS system 900 g, in accordance with other embodiments of thepresent invention. The system 900 g includes a cuff portion 950 gconfigured to wrap around both the carotid artery 906L and the vagusnerve 910L. The electrode contacts for both the CBS electrode assemblyand the VNS electrode assembly are provided on an interior surface ofthe single cuff portion 950 g. Because of the close proximity of thecarotid artery 906L to the vagus nerve 910L, it may be desirable toutilize a single component for coupling to both the carotid artery 906Lto the vagus nerve 910L in order to reduce the number of implantedcomponents and/or simplify implantation. In some embodiments, the cuffportion 950 g, which comprises a single structure that wraps around boththe carotid artery 906L and the vagus nerve 910L, may include acylindrical CBS sub-cuff that wraps around only the carotid artery 906Land includes the electrode contacts for the CBS electrode assembly and acylindrical VNS sub-cuff that wraps around only the vagus nerve 910L andincludes the electrode contacts for the VNS electrode assembly.

It will be understood that the configurations described in the variousembodiments described above may vary to replace single lead assemblieswith single bifurcated lead assemblies or two lead assemblies. Forexample, in FIG. 9F, the two bifurcated lead assemblies 936 f-1 and 936f-2 may be replaced with single lead assemblies, similar to leadassembly 930 a in FIG. 9A or lead assembly 930 b in FIG. 9B.

In some embodiments described above, the pulse generation module, CBSelectrode assemblies, and VNS electrode assemblies may be positioned onthe same side of the patient's body. In other embodiments, one or moreof these components of the VNS/CBS system may be positioned on differentsides of the body. In particular, in some patients, it may be desirablefor the VNS stimulation to be applied to the right vagus nerve, whileproviding CBS stimulation to the left baroreceptor.

In some embodiments, physiological sensors (e.g., ECG electrodes) may bepositioned on one or more of the lead assemblies, the pulse generationmodule, or other structure, such as a separate sensor having a wired orwireless connection with the pulse generation module. In someembodiments, a respiration sensor may be provided along the leadassembly near the VNS electrode or the CBS electrode for sensingrespiratory activity in the throat.

In some embodiments, the VNS functionality and the CBS functionality mayoperate independently, such that VNS stimulation is provided inaccordance with any desired VNS therapeutic modality, and the CBSfunctionality is provided in accordance with any desired CBS therapeuticmodality, without any coordination between the two therapies. In otherembodiments, the control system 1030 of the VNS/CBS system maycoordinate the VNS and CBS stimulation to provide improved therapeuticeffect, as described above.

It will be understood that the VNS/baroreceptor stimulation systemsdescribed above are merely exemplary, and in other embodiments,different configurations may be used.

In various embodiments described above, the patient's heart rateresponse is used as the patient parameter indicative of the desiredphysiological response to VNS, and ECG is used to determine when changesto the CBS therapy are to occur. In other embodiments, different patientparameters may be monitored in conjunction with stimulation, including,for example, other heart rate variability parameters, ECG parameterssuch as PR interval and QT interval, and non-cardiac parameters such asrespiratory rate, pupil diameter, and skin conductance. Increases anddecreases in these patient parameters in response to changes instimulation intensity may be used to identify the desired physiologicalresponse.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A method of operating an implantableneurostimulation system, comprising: delivering a carotid baroreceptorstimulation (CBS) therapy to carotid baroreceptors of a patient for atreatment of chronic heart failure, according to a set of parameters,with a pulse generator; determining an activity level of the patient;and modifying the set of parameters of the CBS therapy based on thedetermined activity level.
 2. The method according to claim 1, furthercomprising: detecting subcutaneous electrocardiographic (ECG) signals;and determining, based on the ECG signals, a change in a heart rate inresponse to the CBS therapy.
 3. The method according to claim 1,wherein: determining the activity level of the patient comprisesestimating when the patient is in a sleep state; and the set ofparameters of the CBS therapy are modified when the patient is estimatedto be in the sleep state.
 4. The method according to claim 1, wherein:delivering the CBS therapy comprises delivering the CBS therapy via aCBS electrode assembly electrically coupled to the carotidbaroreceptors.
 5. The method according to claim 4, wherein the CBSelectrode assembly is provided on a cuff portion of a lead assembly, thecuff portion configured to wrap around a carotid artery.
 6. The methodaccording to claim 1, wherein: delivering the CBS therapy comprisesdelivering electrical stimulation via a first CBS electrode assemblyelectrically coupled to a first carotid baroreceptor region anddelivering electrical stimulation via a second CBS electrode assemblyelectrically coupled to a second baroreceptor region.
 7. The methodaccording to claim 1, wherein delivering the CBS therapy comprises:delivering electrical stimulation via a first CBS electrode assemblyelectrically coupled to a first carotid baroreceptor region and providedat a distal end of a first CBS lead portion; and delivering electricalstimulation via a second CBS electrode assembly electrically coupled toa second carotid baroreceptor region and provided at a distal end of asecond CBS lead portion, the first CBS lead portion and the second CBSlead portion coupled to a bifurcated portion of a lead assembly.
 8. Themethod according to claim 1, wherein delivering the CBS therapycomprises: delivering electrical stimulation via a first CBS electrodeassembly electrically coupled to a first carotid baroreceptor region andprovided at a distal end of a first CBS lead portion, the first CBS leadportion coupled to a bifurcated portion of a first lead assembly; anddelivering electrical stimulation via a second CBS electrode assemblyelectrically coupled to a second carotid baroreceptor region andprovided at a distal end of a second CBS lead portion, the second CBSlead portion coupled to a bifurcated portion of a second lead assembly.9. The method according to claim 1, further comprising: delivering avagus nerve stimulation (VNS) therapy to a vagus nerve of the patientfor the treatment of chronic heart failure, according to a second set ofparameters, with the pulse generator.
 10. The method according to claim9, wherein at least a portion of the CBS therapy is provided during asame time during which at least a portion of the VNS therapy isprovided.
 11. A non-transitory computer-readable medium havinginstructions stored thereon that are executable by a processor of animplantable neurostimulation system to cause the processor to performoperations comprising: delivering a carotid baroreceptor stimulation(CBS) therapy to carotid baroreceptors of a patient, according to a setof parameters, with a pulse generator; determining an activity level ofthe patient; and modifying the set of parameters of the CBS therapybased on the determined activity level.
 12. The non-transitorycomputer-readable medium of claim 11, wherein the operations furthercomprise: detecting subcutaneous electrocardiographic (ECG) signals; anddetermining, based on the ECG signals, a change in a heart rate inresponse to the CBS therapy.
 13. The non-transitory computer-readablemedium of claim 11, wherein: determining the activity level of thepatient comprises estimating when the patient is in a sleep state; andthe set of parameters of the CBS therapy are modified when the patientis estimated to be in the sleep state.
 14. The non-transitorycomputer-readable medium of claim 11, wherein the operations furthercomprise: temporarily suspending delivery of the CBS therapy during aperiod of increased activity level of the patient.
 15. Thenon-transitory computer-readable medium of claim 11, wherein theoperations further comprise: delivering the CBS therapy comprisesdelivering bilateral CBS therapy to a first baroreceptor region and asecond baroreceptor region.
 16. The non-transitory computer-readablemedium of claim 11, wherein delivering the CBS therapy comprisesdelivering the CBS therapy via a CBS electrode assembly electricallycoupled to the carotid baroreceptors.
 17. The non-transitorycomputer-readable medium of claim 16, wherein the CBS electrode assemblyis provided on a cuff portion of a lead assembly, the cuff portionconfigured to wrap around a carotid artery.
 18. The non-transitorycomputer-readable medium of claim 11, wherein delivering the CBS therapycomprises delivering electrical stimulation via a first CBS electrodeassembly electrically coupled to a first carotid baroreceptor region anddelivering electrical stimulation via a second CBS electrode assemblyelectrically coupled to a second baroreceptor region.
 19. Thenon-transitory computer-readable medium of claim 11, wherein theoperations further comprise: delivering a vagus nerve stimulation (VNS)therapy to a vagus nerve of the patient, according to a second set ofparameters, with the pulse generator.
 20. The non-transitorycomputer-readable medium of claim 19, wherein at least a portion of theCBS therapy is provided during a same time during which at least aportion of the VNS therapy is provided.